In 1931, the undecapeptide substance P was isolated by Von Euler and Gaddum (Von Euler and Gaddum, 1931). It was named Substance P because of its powdery consistency (Gaddum and Schild, 1934). Substance P (SP) is encoded by the preprotachykinin A-gene (PPT-A) which also comprises the gene sequences of other tachykinins like Neurokinin A (NKA), Neuropeptide K (NPK) and Neuropeptid γ (NP γ) (Carter and Krause, 1990). Neurokinin B is encoded by the PPT II or PPT-B gene. Substance P is expressed in the central nervous system (CNS) as well as in the peripheral nervous system (PNS) (Otsuka and Yoshioka, 1993).
Tachykinins have a variety of functions. They have vasodilatory properties, are responsible for the contraction and relaxation of the smooth muscles in the gastro-intestinal and urogenital tract as well as in the bronchi. Furthermore, tachykinins play a major role in reflexes of defense caused by injuries or conditions of pain. These are, for example, the increase in cardiovascular tonus, vasodilation and triggering the NO-biosynthesis. Substance P has an influence on different inflammatory cells, serves as a neurotransmitter for transmitting pain and has regulatory function in blood formation. The non-Substance P-tachykinin Neurokinin A, Neuropeptide γ as well as Neuropeptide K are likely to play a role as regulators of endocrine functions.
The level of Substance P in body fluids is altered in several diseases. In plasma of sepsis patients a significant increase of the concentration of Substance P was shown well as in plasma and synovial fluid of patients with rheumatoid arthritis (Joyce, Yood and Carraway, 1993).
Substance P also seems to play a role in inflammatory intestinal diseases like Crohn's disease and colitis ulcerosa.
Substance P m-RNA expression is significantly increased in HIV-infected macro-phages, which indicates an effect of that tachykinin in HIV infections.
In the liquor of Alzheimer's patients (late-onset) and patients suffering from amyotrophic lateral sclerosis a significant increase of Substance P is observed.
In Parkinson's disease a reduction or an increase of Substance P in the medial globus pallidus was observed depending on the degree of dopamine reduction in the putamen.
Patients suffering from Chorea Huntington, a genetically dependent neuro-degenerative disease, showed a selective loss of preprotachykinin containing neurons in the brain.
In the serum of patients with cerebral ischemia (transient inhibition of blood flow as well as stroke), a significant increase in concentrations of Substance P could be determined.
Patients having carcinoid tumors showed an increased concentration of Substance P and Neurokinin A in the blood circulation as well as a significant increase in immune reactivity of tachykinin-like metabolites in urine. Substance P and Neurokinin A possibly also play a role in migraine, other subsistence disorders, in the development of glioma and they have a strong influence on the secretion in the bronchial tubes and on the bronchial circulation, which suggests that they might play a possible role as mediators in asthma.
In smokers suffering from a chronic bronchitis a ten-fold increase of PPT-A-mRNA concentration in lung epithelial cells could be shown.
In fibromyalgy and depression the concentration of Substance P in serum and liquor is increased, as well as in serum of patients suffering from sickle cell anemia is increased, especially in phases of pain.
Increased concentrations of Substance P are measured in patients suffering from atopic dermatitis that correlate with the severety of the disease.
Tachykinins like Substance P and Neurokinin A furthermore play a role in the regulation of proinflammatory cytokine responses.
The biosynthesis of the tachykinins starts as preprohormone. During biosynthesis after separation of the hydrophobic N-terminal sequence by so-called signal peptidasis and folding of the proteins in the lumen of the endoplasmic reticulum, the propeptides migrate into the vesicles of the Golgi Apparatus and are transported to the cell membrane. During transport the propeptides are processed to mature hormones by prohormone-convertases at usually dibasic amino acid sequences. Via different stimuli the peptides are secreted into the extracellular space or into the plasma. The mature peptides are rapidly inactivated after secretion by proteolysis. Substance P and Neurokinin A in vivo have an extremely low half-life of less than 2 minutes in blood. Neuropeptide K shows a bi-phasic degradation with a half-life of 0.9 minutes (degradation to Neuropeptide γ) and 6 minutes in plasma (further degradation).
The tachykinin Substance P, Neurokinin A, Neuropeptide K and Neuropeptide γ are encoded by the preprotachykinin A-gene (PPT-A). Alternative splicing of the PPT-A gene transcript results in 4 different mRNA molecules: α PPT-A, β PPT-A, γPPT-A and δPPT-A. All four mRNA molecules contain the sequence of Substance P. Only βPPT-A mRNA contains all 7 exons of the PPTA-gene and thus encodes all 4 tachykinins. Exon 6 is missing in the α PPT-A mRNA and exons 4 and 6 are missing in the δPPT-A mRNA. Thus, only those two types of mRNA encode the complete sequence of Substance P. Exon 4 is missing in γPPT-A mRNA, thus Neuropeptide K cannot be transcribed from this mRNA. The production of Substance P by all 4 splice variants suggests that when the PPT-A gene is expressed, also Substance P is produced. The expression of αPPT-A mRNA occurs predominantly in the brain, while, βPPT-A and γPPT-A mRNA molecules are predominantly expressed in peripheral tissue.
The PTK-A fragment 1-37 plays a central role in this invention and is called A-peptide herein.